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► The accuracy of particle size distribution measurements is technique dependent. ► The disparity between measurements made by different techniques increases with sample complexity ...and polydispersity. ► Only TRPS and DCS techniques resolved all particles present in complex multimodal samples. ► PTA and DLS techniques had lower resolution and reported higher polydispersity than truly present in all test samples. ► All four techniques tested had high repeat measurement precision.
The particle size distribution (PSD) of a polydisperse or multimodal system can often be difficult to obtain due to the inherent limitations in established measurement techniques. For this reason, the resolution, accuracy and precision of three new and one established, commercially available and fundamentally different particle size analysis platforms were compared by measuring both individual and a mixed sample of monodisperse, sub-micron (220, 330, and 410nm – nominal modal size) polystyrene particles. The platforms compared were the qNano Tunable Resistive Pulse Sensor, Nanosight LM10 Particle Tracking Analysis System, the CPS Instruments’s UHR24000 Disc Centrifuge, and the routinely used Malvern Zetasizer Nano ZS Dynamic Light Scattering system. All measurements were subjected to a peak detection algorithm so that the detected particle populations could be compared to ‘reference’ Transmission Electron Microscope measurements of the individual particle samples. Only the Tunable Resistive Pulse Sensor and Disc Centrifuge platforms provided the resolution required to resolve all three particle populations present in the mixed ‘multimodal’ particle sample. In contrast, the light scattering based Particle Tracking Analysis and Dynamic Light Scattering platforms were only able to detect a single population of particles corresponding to either the largest (410nm) or smallest (220nm) particles in the multimodal sample, respectively. When the particle sets were measured separately (monomodal) each platform was able to resolve and accurately obtain a mean particle size within 10% of the Transmission Electron Microscope reference values. However, the broadness of the PSD measured in the monomodal samples deviated greatly, with coefficients of variation being ∼2–6-fold larger than the TEM measurements across all four platforms. The large variation in the PSDs obtained from these four, fundamentally different platforms, indicates that great care must still be taken in the analysis of samples known to have complex PSDs. All of the platforms were found to have high precision, i.e. they gave rise to less than 5% variance in PSD shape descriptors over the replicate measurements.
For approval, a proposed generic drug product must demonstrate it is bioequivalent (BE) to the reference listed drug product. For locally acting drug products, conventional BE approaches may not be ...feasible because measurements in local tissues at the sites of action are often impractical, unethical, or cost‐prohibitive. Mechanistic modeling approaches, such as physiologically‐based pharmacokinetic (PBPK) modeling, may integrate information from drug product properties and human physiology to predict drug concentrations in these local tissues. This may allow clinical relevance determination of critical drug product attributes for BE assessment during the development of generic drug products. In this regard, the Office of Generic Drugs of the US Food and Drug Administration has recently established scientific research programs to accelerate the development and assessment of generic products by utilizing model‐integrated alternative BE approaches. This report summarizes the presentations and panel discussion from a public workshop that provided research updates and information on the current state of the use of PBPK modeling approaches to support generic product development for ophthalmic, injectable, nasal, and implant drug products.
The pharmaceutical industry as well as European and US governing agencies have indicated the need for more accurate, high resolution, characterization of complex drug materials, nanomedicines, to ...facilitate their development and eventual approval. In particular, accurately measuring the size, zeta-potential, and concentration of nanomedicines is desired. Herein we demonstrate the comprehensive and high resolution analysis capabilities of tunable resistive pulse sensing (TRPS) on the most widely approved nanomedicines to-date, liposomal particles. The number-based size distribution, concentration and volume fraction of liposomes formed by extrusion through a 100 nm or 200 nm Nucleopore filter membrane are shown as well as how freeze-thaw aggregation changes individual liposomes and the overall size distribution. In addition, the simultaneous size and zeta-potential analysis capabilities of TRPS is used to characterize the homogeneity and difference between liposomes made with and without the addition of PEGylated phospholipids.
Amphotericin B (AmB) is an amphiphilic drug commonly formulated in liposomes and administered intravenously to treat systemic fungal infections. Recent studies on the liposomal drug product have shed ...light on the AmB aggregation status in the bilayer, which heat treatment (curing) modifies. Although toxicity was found related to aggregation status - loose aggregates significantly more toxic than tight aggregates - the precise mechanism linking aggregation and toxicity was not well understood. This study directly measured drug release rate from various AmB liposomal preparations made with modified curing protocols to evaluate correlations among drug aggregation state, drug release, and in vitro toxicity. UV–Vis spectroscopy of these products detected unique curing-induced changes in the UV spectral features: a ∼25 nm blue-shift of the main absorption peak (λmax) in aqueous buffer and a decrease in the OD346/OD322 ratio upon thermal curing, reflecting tighter aggregation. In vitro release testing (IVRT) data showed, by applying and fitting first-order release kinetic models for one or two pools, that curing impacts two significant changes: a 3–5-fold drop in the overall drug release rate and a ten-fold decrease in the ratio between the loosely aggregated and the tightly aggregated, more thermodynamically stable drug pool. The kinetic data thus corroborated the trend independently deduced from the UV–Vis spectral data. The in vitro toxicity assay indicated a decreased toxicity with curing, as shown by the significantly increased concentration, causing half-maximal potassium release (TC50). The data suggest that the release of AmB requires dissociation of the tight complexes within the bilayer and that the reduced toxicity relates to this slower rate of dissociation. This study demonstrates the relationship between AmB aggregation status within the lipid bilayer and drug release (directly measured rate constants), providing a mechanistic link between aggregation status and in vitro toxicity in the liposomal formulations.
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► We review recent progress in pore sensors for characterizing dispersion properties. ► We highlight the potential and current limitations of classic pore sensors. ► A detailed ...analysis of three new types of sensors and their benefits is included. ► These new sensors offer improved sample throughput and measurement sensitivity.
Since the first reported use of a biological ion channel to detect differences in single stranded genomic base pairs in 1996, a renaissance in nanoscale resistive pulse sensors has ensued. This resurgence of a technique originally outlined and commercialized over 50 years ago has largely been driven by advances in nanoscaled fabrication, and ultimately, the prospect of a rapid and inexpensive means for genomic sequencing as well as other macromolecular characterization. In this pursuit, the potential application of these devices to characterize additional properties such as the size, shape, charge, and concentration of nanoscaled materials (10–900
nm) has been largely overlooked. Advances in nanotechnology and biotechnology are driving the need for simple yet sensitive individual object readout devices such as resistive pulse sensors. This review will examine the recent progress in pore-based sensing in the nanoscale range. A detailed analysis of three new types of pore sensors – in-series, parallel, and size-tunable pores – has been included. These pores offer improved measurement sensitivity over a wider particle size range. The fundamental physical chemistry of these techniques, which is still evolving, will be reviewed.
The prospect of characterizing individual nanoparticles, molecules, or DNA base pairs has generated considerable interest in resistive pulse sensing. In addition to size and concentration analysis, ...this technique also has the capacity to measure the charge density of objects in situations where electrophoretic forces dominate their motion. Here we present a methodology to simultaneously extract, via appropriate theoretical models, the size and ζ-potential of objects from the resistive pulse signal they generate. The methodology was demonstrated using a size-tunable elastic pore sensor to measure a complex “bimodal” suspension composed of two particle sets with different size and charge. Elastically tuning the size of the pore sensor, by stretching the elastic pore membrane, enables a larger sample size range to be analyzed, improves measurement sensitivity, and fine-tunes the forces acting on objects. This methodology represents a new approach for investigating and understanding the fundamental behavior of nanoscale dispersions.
Performance evaluation of polydimethylsiloxane (PDMS) based long-acting (e.g. 3–5 years) levonorgestrel (LNG) intrauterine systems (IUSs), such as Mirena®, is challenging due to their complex ...formulation, locally-acting feature, and extremely long duration of drug release. To achieve such long-term release, a large amount of drug (up to 52 mg in Mirena®) must be incorporated as a drug reservoir in the IUS. Consequently, dose dumping or unanticipated changes in the LNG-IUS in vivo release characteristics may give rise to adverse product safety and efficacy. Therefore, it is crucial to understand, and have appropriate control over, the physicochemical properties and in vitro release characteristics of these products. This requires an understanding of the LNG-IUSs drug release mechanism and the development of a sensitive yet robust in vitro release testing method. There have been no previous reports on in vitro drug release and the release mechanism from LNG-IUSs. This is probably a consequence of the extremely slow drug release rate of LNG-IUSs under real-time in-use conditions (e.g., 3–5 years) and therefore it is impractical to obtain complete release profiles (e.g. there is only 60% release in 5 years for Mirena®). Therefore, the development of appropriate accelerated in vitro release methods is imperative. Following preparation of LNG-IUSs, similar to Mirena®, real-time release was tested in (0.9% w/v NaCl) media in a water shaker bath at 37 °C for over 2 years. Addition of surfactant (sodium dodecyl sulfate (SDS)), elevation of temperature, addition of organic solvents (ethanol (EtOH), isopropanol (IPA), tert-butanol (TBA) and tetrahydrofuran (THF)) and a combination thereof were utilized as release media to accelerate drug release for LNG-IUSs. Complete drug release was achieved in 32 and 672 days in THF and TBA hydro-organic media, respectively. The release profile in THF was considered too fast as it may result in change of release mechanism, whereas the release profile in TBA was deemed suitable following model fitting. Model fitting was performed to understand the release characteristics as well as the release mechanisms. The release rate in the hydro-alcoholic media was linearly proportional to the swelling ratio of the PDMS in the corresponding organic solvents. Zero-order, first-order and two-phase models were utilized to fit the release profiles obtained under the different release conditions. The data analysis was comparable using the parameters from different models given the high R2 values. However, the two-phase model was better in terms of the release mechanism of the LNG-IUSs considering the full drug release profile. The present study will facilitate the process of granting of biowaivers through an in vitro approach, thus reducing the necessity for clinical studies. In addition, it will help reduce the regulatory burden without sacrificing product quality of LNG-IUS products.
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The purpose of this study is to investigate the process of drug distribution and mechanism of drug release of ophthalmic emulsions in the context of factors associated with the drug release. ...Cyclosporine and difluprednate emulsions were chosen as model systems. A kinetic method was used to quantitatively evaluate the drug distribution within a simplified biphasic (emulsion) system. The impacts of release associated factors were investigated, including the amount of sodium dodecyl sulfate (SDS), ethanol, and ionic strength in the release medium as well as the temperature. SDS and ethanol were found to significantly enhance both rate and extent of drug diffusion from oil to aqueous phase for both cyclosporine and difluprednate emulsions. The ionic strength was found to decrease the rate and extent of cyclosporine transfer from oil to aqueous phase but had little impact on the transfer of difluprednate between phases. Diffusion of cyclosporine to aqueous phase exhibited a decreasing trend with increasing temperature due to its atypical temperature dependent solubility in water. Based on our previous method to investigate the impact of formulation variables on drug diffusion and the findings in the current study, a biphasic release model for emulsions is proposed and discussed. Lastly, the underlying relationship of three key quality attributes (i.e., globule size distribution, drug distribution, and release characteristics) and their effect on product quality and performance were discussed. This study provides a fundamental insight into the drug distribution and release in complex emulsion systems. It also elucidates the critical variables for the development of in vitro release method to support regulatory assessment of ophthalmic emulsions and formulation development.
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•The process of drug distribution and mechanism of drug release of ophthalmic emulsions are investigated in the study.•The evaluated factors include the amount of SDS, ethanol and ionic strength in release medium as well as the temperature.•The effect of globule size distribution, drug distribution and release on performance of ophthalmic emulsion is elucidated.
NMR spin−spin solvent relaxation measurements have been performed on a series of aqueous dispersions of silica with physisorbed poly(ethylene oxide) (PEO) and poly(vinyl pyrrolidone) (PVP). ...Enhancements in the specific relaxation rate constant as a result of polymer adsorption were observed. Measurements of the relaxation rate constant as a function of the concentrations of silica and polymer in the system have been used to determine the amount of polymer trains adsorbed at the particle surface, at saturation. Studies of PEO−PVP−silica dispersions have shown that preadsorbed PEO is completely displaced when the silica concentration is small enough to allow the added PVP to saturate the surface. When the concentration of silica is increased beyond this point, then PEO and PVP are able to coexist on the particle surface.
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